N-substituted pyrrolidine derivatives and process for preparing the same

ABSTRACT

Novel N-substituted pyrrolidine derivatives having a highly selective and potent antagonism against smooth muscle muscarine receptors and being useful for the treatment of irritable bowel syndrome and the like, characterized by being represented by general formula (1) wherein R represents a hydrogen atom, a halogen atom, or a lower alkoxy group and a process for preparing the same.

This application is a 371 of PCT/JP97/04306 Nov. 26, 1997.

TECHNICAL FIELD

The present invention relates to novel N-substituted pyrrolidinederivatives having a highly selective and potent antagonism againstsmooth muscle muscarine receptors rather than cardiac muscarinereceptors and being useful for the treatment of altered smooth musclemotility and tone, such as irritable bowel syndrome, diverticulosis,urinary incontinence, esophageal achalasia and chronic obstructiveairway disease, and process for preparing the same.

BACKGROUND TECHNOLOGIES

As one of the therapeutic drugs for the irritable bowel syndrome, theanticholinergic agent has been used, but it brings no sufficienttherapeutic effect due to, in part, deficit of tissue selectivity. Also,while compounds that was reported to have a selective antagonism againstsmooth muscle muscarine receptors are disclosed (Japanese UnexaminedPatent Publication Nos. Hei 2-282360 and Hei 7-149640, these compoundsalso do not sufficiently solve the adverse effect such as mydriasis.Moreover, these compounds have diphenylalkyl moiety linked to carbonatom of the pyrrolidine ring, making them different from the structureof the inventive compounds, in which it links to the nitrogen atom ofthe pyrrolidine ring.

The invention is to provide novel N-substituted pyrrolidine derivativeshaving a highly selective and potent antagonism against smooth musclemuscarine receptors and being useful for the treatment of irritablebowel syndrome and the like.

As a result of diligent studies directed toward the development of thedrug exhibiting a highly selective and potent antagonism against smoothmuscle muscarine receptors and less adverse effect of mydriasis, theinventors have found that novel N-substituted pyrrolidine derivativesrepresented by the following general formula (1) have high safety andare useful for the treatment of irritable bowel syndrome and the like,leading to the completion of the invention.

Namely, the invention relates to N-substituted pyrrolidine derivativesrepresented by the general formula (1) ##STR1## [wherein R denotes ahydrogen atom, a halogen atom or a lower alkoxy group], pharmaceuticallyacceptable salt, and a therapeutic drug for the irritable bowel syndromeand the like having at least one or more kinds of them as effectiveingredients.

For the pharmaceutically acceptable salts of the compounds representedby the general formula (1) in the invention, acid adducts such ashydrochloride, hydrobromide, benzenesulfonate, citrate, fumarate,gluconate, lactate, maleate, methanesulfonate, succinate and tartrateare mentioned.

For the "lower alkoxy groups" in the invention, straight chain orbranched ones with carbon atoms of 1 to 6 such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy,isopentoxy, tert-pentoxy, neopentoxy, hexoxy, isohexoxy, sec-hexoxy andtert-hexoxy are mentioned.

For the "halogen atoms", fluorine, chlorine, bromine and iodine atomsare mentioned.

According to the invention, compounds represented by the general formula(1) can be prepared through the following process. ##STR2## [wherein Ris as described above].

Compounds having the general formula (1) can be prepared by hydrolyzingthe compounds represented by the general formula (4) ##STR3## [wherein Ris as described above].

In the case of the use of the acid catalyst, the hydrolysis is performedunder heat, preferably at 70 to 110° C., using, for example, inorganicacid such as concentrated sulfuric acid. On the other hand, in the caseof the alkali hydrolysis, it can be performed in alcohol, using, forexample, alkali metal hydroxide such as sodium hydroxide or potassiumhydroxide, and it is preferable to perform in refluxing tert-butanolwith potassium hydroxide.

Compounds having the general formula (4) are also novel compounds andcan be prepared by the reaction of the compounds represented by thegeneral formula (3) with the compounds represented by the generalformula (2), or by the reaction of the compound represented by thegeneral formula (3) that was prepared by the deprotection of thecompound represented by the general formula (3-a). ##STR4## [wherein Xdenotes a halogen atom]. ##STR5## [wherein R is as described above, andBoc denotes a tert-butoxycarbonyl group].

The reaction can be performed, according to normal process, by thereaction of the compounds represented by the general formula (3) withcompounds represented by the general formula (2) in the presence ofinorganic base or organic base, or by the treatment of the protectinggroup of the compounds represented by the general formula (3-a) withtrifluoroacetic acid or the like and then react with the compoundsrepresented by the general formula (2).

Compounds represented by the general formula (3) obtained by thedeprotection of the compounds represented by the general formula (3-a)can be used for the next step without isolation of the deprotectedproduct. At this time, as the bases, organic bases such as triethylamineare preferable. Moreover, for the solvents, inert solvents such asN,N-dimethylformamide, dimethyl sulfoxide and N-methyl-2-pyrrolidone canbe used, but, thereamong, N-methyl-2-pyrrolidone is preferable. Thereaction could be performed preferably at room temperature to 200° C.,preferably at 100° C. to 150° C.

Best embodiment to put the invention into practice

In following, the invention will be illustrated based on the concreteexamples, but the invention is not confined to these examples. Besides,with the compounds of the invention, there exist optical isomers basedon the 3-position of the asymmetric carbon of the pyrrolidine ring,which are all included. In addition, hydrates of the compounds of theinvention are all included similarly within the scope of the invention.

Besides, the abbreviations used in the invention have followingmeanings.

MS Mass spectrum

¹ H-NMR Proton nuclear magnetic resonance spectrum

NMP N-methyl-2-pyrrolidone

FAB MS Fast atomic bombardment mass spectrum

EXAMPLE 1

Preparation of4-[3-(3-chlorobenzyloxy)pyrrolidine-1-yl]-2,2-diphenylbutyronitrile

To 20 ml of NMP was added 2,54 g of 4-bromo-2,2-diphenylbutyronitrile,1.79 g of 3-(3-chlorobenzyloxy)pyrrolidine and 1.29 g of triethylamine,and the mixture was stirred for 20 hours at 140° C. The reaction mixturewas concentrated under reduced pressure and water was added to theresidue, and then extracted with methylene chloride. The extract wasdried over anhydrous sodium sulfate. The organic layer was concentratedand the residue was purified by silica gel column chromatography (ethylacetate) to obtain 1.81 g of the aimed compound as a brown oil.

FAB MS: 431[M+H]⁺

EXAMPLES 2 through 4

Similarly to Example 1, the following compounds were obtained.

    ______________________________________                                         ##STR6##                                                                     No. of example                                                                             R          FAB MS [M + H].sup.+                                  ______________________________________                                        2            H          397                                                   3            3-Cl (R form)                                                                            431                                                   4            3-Cl (S form)                                                                            431                                                   ______________________________________                                    

EXAMPLE 5

Preparation of4-[3-(3-fluorobenzyloxy)pyrrolidine-1-yl]-2,2-diphenylbutyronitrile

To 2.0 g of 1-tert-butroxycarbonyl-3-(3-fluorobenzyloxy) pyrrolidine wasadded 10 ml of trifluoroacetic acid under cooling with ice and stirring,then the mixture was stirred for 30 minutes at 0° C., then excesstrifluoroacetic acid was distilled off. To the residue was added 2.0 gof 4-bromo-2,2-diphenylbutyronitrile, 2.0 g of triethylamine and 20 mlof NMP, and the mixture was stirred for 16 hours at 140° C. The reactionmixture was concentrated under reduced pressure and methylene chloridewas added to the residue, then washed with water. After drying overanhydrous sodium sulfate, the organic layer was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (ehtyl acetate) to obtain 0.53 g of the aimed compound asa brown oil.

FAB MS: 415[M+H]⁺

EXAMPLES 6 through 8

Similarly to Example 5, the following compounds were obtained.

    ______________________________________                                         ##STR7##                                                                     No. of example                                                                              R       FAB MS [M + H].sup.+                                    ______________________________________                                        6             4-Cl    431                                                     7             4-F     415                                                     8             3-MeO   427                                                     ______________________________________                                    

EXAMPLE 9

Preparation of4-[3-(3-chlorobenzyloxy)pyrrolidine-1-yl]-2,2-diphenylbutaneamide

To 1.80 g of4-[3-(3-chlorobenzyloxy)pyrrolidine-1-yl]2,2-diphenylbutyronitrile wasadded 1.41 g of potassium hydroxide and 15 ml of tert-butanol, and themixture was refluxed for 48 hours. The reaction mixture was poured intoice water, then extracted with methylene chloride, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (methylenechloride:methanol=10:1) to obtain 1.57 g of the aimed compound as ayellow oil.

MS: 448(M⁺)

Elemental analysis (%): As C₂₇ H₂₉ ClN₂ O₂.1/5H₂ O

    ______________________________________                                                C           H      N                                                  ______________________________________                                        Calcd.    71.65         6.54   6.18                                           Found     71.36         6.52   6.17                                           ______________________________________                                    

EXAMPLES 10 through 14

Similarly to Example 9, the following compounds were obtained.

    __________________________________________________________________________     ##STR8##                                                                                                Elemental analysis (%)                             No. of                     Calcd./Found                                       example                                                                            R   Composition formula                                                                       Property                                                                            C  H   N                                           __________________________________________________________________________    10   H   C.sub.27 H.sub.30 N.sub.2 O.sub.2.1/2H.sub.2 O                                            Amorphous                                                                           76.57                                                                            7.38                                                                              6.61                                                                   76.89                                                                            7.31                                                                              6.56                                        11   4-Cl                                                                              C.sub.27 H.sub.29 ClN.sub.2 O.sub.2.H.sub.2 O                                             Amorphous                                                                           69.44                                                                            6.69                                                                              6.00                                                                   69.38                                                                            6.58                                                                              5.83                                        12   3-F C.sub.27 H.sub.29 FN.sub.2 O.sub.2.H.sub.2 O                                              Amorphous                                                                           71.98                                                                            6.94                                                                              6.22                                                                   71.72                                                                            6.75                                                                              6.23                                        13   4-F C.sub.27 H.sub.29 FN.sub.2 O.sub.2.H.sub.2 O                                              Amorphous                                                                           71.98                                                                            6.94                                                                              6.22                                                                   71.93                                                                            6.84                                                                              6.33                                        14   3-MeO                                                                             C.sub.28 H.sub.32 N.sub.2 O.sub.3.3/2H.sub.2 O                                            Amorphous                                                                           71.31                                                                            7.48                                                                              5.94                                                                   71.11                                                                            7.15                                                                              6.07                                        __________________________________________________________________________

EXAMPLES 15

Preparation of(R)-4-[3-(3-chlorobenzyloxy)pyrrolidine-1-yl]-2,2-diphenylbutaneamide

Using 8.93 g of(R)-4-[3-(3-chloroenzyloxy)pyrrolidine-1-yl]-2,2-diphenylbutyronitrileobtained in Example 3, procedure was taken similarly to Example 9 toobtain 7.88 g of the aimed compound as an oil.

Since this oil crystallized after standing, it was recrystallized fromdiisopropyl ether to obtain the aimed compound as white powderycrystals.

Melting point: 91.0˜93.0° C.

Angle of rotation: [α]_(D) : -5.1 (C=1.3, MeOH)

Elemental analysis (%): As C₂₇ H₂₉ ClN₂ O₂.2/5H₂ O

    ______________________________________                                                C           H      N                                                  ______________________________________                                        Calcd.   71.09          6.58   6.14                                           Found    71.07          6.42   6.12                                           ______________________________________                                    

EXAMPLE 16

Preparation of(S)-4-[3-(3-chlorobenzyloxy)pyrrolidine-1-yl]-2,2-diphenylbutaneamide

Using 460 mg of4-[3(S)-(3-chlorobenzyloxy)pyrrolidine-1-yl]-2,2-diphenylbutyronitrileobtained in Example 4, procedure was taken similarly to Example 9 toobtain 413 mg of the aimed compound as an oil.

Angle of rotation: [α]_(D) : 5.1 (C=1.1, MeOH)

Elemental analysis (%): As C₂₇ H₂₉ ClN₂ O₂.2/5H₂ O

    ______________________________________                                                C           H      N                                                  ______________________________________                                        Calcd.   71.09          6.58   6.14                                           Found    71.00          6.80   5.92                                           ______________________________________                                    

EXPERIMENTAL EXAMPLE

1. Antagonism on the acetylcholine-induced contraction of ileum (invitro test)

Hartley male guinea pig was killed by stunning and bleeding. The ileumwas removed to make a 1.5 to 2 cm preparation. The preparation wasmounted in a 10 ml organ bath filled with Tyrode's solution of 28° C.that was bubbled with 95% O₂ /5% CO₂. The initial resting tension of 1 gwas applied to the preparation and measurement of isomeric muscletension was recorded.

The action of testing drug is shown in terms of pA₂ determined fromSchild plot of the extent of right shift of the concentration-responsecurve on 10⁻⁹ M˜3×10⁻⁶ M of acetylcholine.

2. Antagonism on the acetylcholine-induced contraction of pupil (invitro test)

Japanese white male rabbit was anesthetized using sodium pentobarbitaland killed by bleeding. The eyeball was removed to make a preparation ofsphincter muscle of the pupil. The preparation was mounted in a 10 mlorgan bath filled with Krebs solution of 30° C. that was bubbled with95% O₂ /5% CO₂. The initial resting tension of 0.2 g was applied to thepreparation and measurement of isometric muscle tension was recorded.

The action of testing drug is shown in terms of pA₂ determined fromSchild plot of the extent of right shift of the concentration-responsecurve on 10⁻⁶ M˜10⁻² M of acetylcholine.

3. Antagonism action on the acetylcholine-induced negative chronotropicaction of atrium of heart (in vitro test)

Hartley male guinea pig was killed by stunning and bleeding. The heartwas removed to make a preparation of atrium of heart. The preparationwas mounted in a 10 ml organ bath filled with Krebs-Henseleit solutionof 32° C. that was bubbled with 95% O₂ /5% CO₂. The initial restingtension was made to be 0.5 g and measurement of isometric muscle tensionwas recorded.

The action of testing drug is shown in terms of pA₂ determined fromSchild plot of the extent of right shift of the concentration-responsecurve on 10⁻⁹ M˜3×10⁻⁶ M of acetylcholine.

4. Inhibitory effect in the defecation model under restraint stress (invivo test)

Wistar strain male rats were employed. Testing drug was administeredorally at 10 mg/kg and, after 30 minutes, the restraint stress was givenby fixing the forefeet of rat on back side under anesthetization withether. Moreover, the diameter of pupil (mm) was also measured.

After allowed to stand for 1 hour in separate cage, the defecation leveland diameter of pupil were measured.

The inhibitory rate of defecation was determined from following formula.

    __________________________________________________________________________     ##STR9##                                                                     Results from above are shown in following table.                                                  In vivo test                                                     In vitro test                                                                              Inhibitory                                                                            Diameter of pupil (mm)                                   pA.sub.2     rate of Immediately                                                                          After                                             Ileum                                                                             Pupil                                                                             Atrium                                                                             defecation (%)                                                                        after restraint                                                                      restraint                                  __________________________________________________________________________    Example 9                                                                            7.6 7.3 6.2  48.9    0.43*  0.45**                                     __________________________________________________________________________     *Control 0.44,                                                                **Control 0.48                                                           

From the results obtained above, the inventive compound exhibitedexcellent anticholinergic activity and, based on its action, it showedan effect of inhibited defecation level. In addition, the inventivecompound exhibited higher selectivity against ileum muscarine receptorsthan heart muscarine receptors.

Against ileum, in particular, it exhibited the selectivity over 10 timeshigher than that against atrium of heart. Moreover, it was suggestedfrom in vivo test that it exerted little influence particularly againstpupil.

Utilizability in the industry

From the facts above, the compounds of the invention are effective forthe treatment of irritable bowel syndrome and the like and are useful asmedicinal drugs with high tissue selectivity and less adverse effects onheart and pupil.

We claim:
 1. N-substituted pyrrolidine derivatives represented by thegeneral formula (1) ##STR10## [wherein R denotes a hydrogen atom, ahalogen atom or a lower alkoxy group], and pharmaceutically acceptablesalts.
 2. A process for preparing compounds represented by the generalformula (4) ##STR11## [wherein R denotes a hydrogen atom, a halogen atomor a lower alkoxy group], characterized by reacting compoundsrepresented by the general formula (3) ##STR12## [wherein R is asdescribed above], with compounds represented by the general formula (2)##STR13## [wherein X denotes a halogen atom].
 3. A process for preparingN-substituted pyrrolidine derivatives represented by the general formula(1) ##STR14## [wherein R denotes a hydrogen atom, a halogen atom or alower alkoxy group], characterized by hydrolyzing compounds representedby the general formula (4) ##STR15## [wherein R is as described above].4. The compound4-(3-(3-chlorobenzyloxy)pyrrolidine-1-yl)-2,2-diphenylbutaneamide.
 5. Ahydrate of the N-substituted pyrrolidine derivative of claim
 1. 6. Ahydrate of the compound of claim
 4. 7. A method for treatment ofirritable bowel syndrome in a patient which comprises administering tosaid patient a therapeutically effective amount of a compound accordingto claim 1.